TY - JOUR
T1 - Disease variants of FGFR3 reveal molecular basis for the recognition and additional roles for Cdc37 in Hsp90 Chaperone system
AU - Bunney, Tom D.
AU - Inglis, Alison J.
AU - Sanfelice, Domenico
AU - Farrell, Brendan
AU - Kerr, Christopher J.
AU - Thompson, Gary S.
AU - Masson, Glenn R.
AU - Thiyagarajan, Nethaji
AU - Svergun, Dmitri I.
AU - Williams, Roger L.
AU - Breeze, Alexander L.
AU - Katan, Matilda
N1 - Funding Information:
We thank A. Hussain, H. Patani, C. Pilotti, V. Dorovykh, N. Vajpai, H. Koss, D. Kent, and D. Bhalsod for supporting contributions. We are very grateful to C. Vaughan and B. Wallace for extremely helpful discussions. We acknowledge the use of the ISMB Biophysics Center and the support of T. Daviter. The M.K. laboratory is supported by Cancer Research UK ( A16567 ). A.L.B. acknowledges access to the Astbury BioStructure Laboratory BioNMR Facility (University of Leeds), which was funded by the Wellcome Trust (grant number 104920/Z/14/Z ) and the University of Leeds , and thanks A. Kalverda for NMR technical assistance. B.F. is supported by a Wellcome Trust studentship ( 109155/Z/15/Z ).
Publisher Copyright:
© 2018 The Authors
PY - 2018/3/6
Y1 - 2018/3/6
N2 - Receptor tyrosine kinase FGFR3 is involved in many signaling networks and is frequently mutated in developmental disorders and cancer. The Hsp90/Cdc37 chaperone system is essential for function of normal and neoplastic cells. Here we uncover the mechanistic inter-relationships between these proteins by combining approaches including NMR, HDX-MS, and SAXS. We show that several disease-linked mutations convert FGFR3 to a stronger client, where the determinant underpinning client strength involves an allosteric network through the N-lobe and at the lobe interface. We determine the architecture of the client kinase/Cdc37 complex and demonstrate, together with site-specific information, that binding of Cdc37 to unrelated kinases induces a common, extensive conformational remodeling of the kinase N-lobe, beyond localized changes and interactions within the binary complex. As further shown for FGFR3, this processing by Cdc37 deactivates the kinase and presents it, in a specific orientation established in the complex, for direct recognition by Hsp90.
AB - Receptor tyrosine kinase FGFR3 is involved in many signaling networks and is frequently mutated in developmental disorders and cancer. The Hsp90/Cdc37 chaperone system is essential for function of normal and neoplastic cells. Here we uncover the mechanistic inter-relationships between these proteins by combining approaches including NMR, HDX-MS, and SAXS. We show that several disease-linked mutations convert FGFR3 to a stronger client, where the determinant underpinning client strength involves an allosteric network through the N-lobe and at the lobe interface. We determine the architecture of the client kinase/Cdc37 complex and demonstrate, together with site-specific information, that binding of Cdc37 to unrelated kinases induces a common, extensive conformational remodeling of the kinase N-lobe, beyond localized changes and interactions within the binary complex. As further shown for FGFR3, this processing by Cdc37 deactivates the kinase and presents it, in a specific orientation established in the complex, for direct recognition by Hsp90.
KW - cancer
KW - Cdc37 cochaperone
KW - client kinases
KW - disease-linked mutations
KW - fibroblast growth factor receptors
KW - Hsp90 chaperone
KW - protein folding
KW - structural and mechanistic insights
UR - http://www.scopus.com/inward/record.url?scp=85042333743&partnerID=8YFLogxK
U2 - 10.1016/j.str.2018.01.016
DO - 10.1016/j.str.2018.01.016
M3 - Article
C2 - 29478821
AN - SCOPUS:85042333743
SN - 0969-2126
VL - 26
SP - 446-458.e8
JO - Structure
JF - Structure
IS - 3
ER -
